The experiments in this grant application propose to use animal models to describe the regulation of neuroendocrine systems during stress. It is hoped that the results of these studies will begin to elucidate why these systems become dysregulated in human depression. Changes in both the hypothalamic-pituitaryadrenal axis (HPA) and the hypothalamic-pituitary-thyroid axis (HPT) have been documented in depressed patients. The activity and regulation of these neuroendocrine systems will be characterized in adult male rats using a paradigm that has been considered an animal model of depression. The paradigm is the controllable/non-controllable (C/NC) stress paradigm. In this paradigm one animal, the executive animal, can terminate his stress (a mild-electric foot shock), but his yoked partner cannot. Both stress groups receive an identical physical stressor, but differ in the psychological aspect of coping. The yoked animals exhibit escape from the suppressive effects of dexamethasone (DEX) on the HPA axis, as do depressed patients. Furthermore, recent work from our lab has also demonstrated that yoked animals, but not executive, have decreased levels of thyroid hormone levels; decreased in thyroid hormone levels have also been linked to human depression. In the proposed experiments, neuropeptide mRNA and hnRNA levels will be measured in the hypothalamus to characterize central drive to both the HPA and HPT axis during and after C/NC stress. These neuropeptide mRNA and hnRNA levels will also be determined in executive and yoked animals pre-treated with DEX. The ability of DEX to penetrate the brain and activate glucocorticoid receptors will also be determined in executive and yoked animals. The results of these studies will fully characterize activity of both the HPA and HPT axis in executive and yoked animals, and also help elucidate the mechanisms underlying escape from DEX suppression. The effects of repeated exposure to either C/NC stress will also be determined. Changes in basal and stress-induced changes in hormone levels will be measured after 7 or 14 days of stress. Changes in neuropeptide mRNA levels will also be determined, along with measurement of Mrna encoding both glucocorticoid, mineralocorticoid, and thyroid hormone receptors. The results of these studies should provide information regarding vital neuroendocrine sytems that often become dysregulated in human depression.